Platelets Play a Protective Role in Erythrocytic Stage Malaria Infection.

Abstract

Abstract MRG-1Mpl-/- mice lack the thrombopoietin receptor (Mpl) and have 10% the platelet mass of normal, isogenic C57BL/6 animals. When infected with the murine malarial parasite, P. chabaudi, C57BL/6 mice survive the infection whereas Mpl-/- mice die. There is a previously, well-documented thrombocytopenia associated with infection by malarial parasites and, in mice, this is co-incidental with a rise in parasitaemia, not the onset of symptoms. We show that murine infected red cells are preferentially bound to platelets. Using the TUNEL staining technique to identify dead or dying cells we show more TUNEL positive cells in C57BL/6 mice than in the thrombocytopenic Mpl-/- mice. Parasites are more likely to be TUNEL positive if their red cell is bound by a platelet or is CD41 positive. This data provided circumstantial evidence that platelet were directly killing malarial parasites within the red cell in the mouse murine model. It was therefore predictable that aspirin should decrease the resistance to malaria and this proved to be the case. The evidence for the protective role of platelets was substantiated by experiments with human platelets and P.falciparum, the lethal human malarial parasite. Unlike the murine malarias, P.falciparum can be grown in culture (with human red cells). The addition of purified human platelets inhibits the growth of P. falciparum. This is associated with an increase in TUNEL-staining of parasites. It is inhibited by most platelet activation inhibitors (aspirin, Prostaglandin E1, sodium nitroprusside, and the P2Y1 antagonist, MRS2179 as well as administration of aspirin to the platelet donor prior to platelet isolation. Interestingly, inhibition of P2Y12 by MRS2395 does not abrogate the growth inhibitory effect of platelets. Again, infected red cells preferentially bind platelets and there is an excellent correlation between the binding of platelets in infected cells and TUNEL positivity of the resident parasite. This data points strongly to the ability of platelets to kill intraerythocytic malarial parasites. In association with the specificity of binding to infected erythrocytes, this provides a further mechanism of innate immunity, mediated by platelets aimed at controlling the growth of malarial parasites. We surmise that its major impact will be early in infection, prior to the onset of significant parasitaemia or thrombocytopenia, at which stage parasite numbers will greatly outnumber platelets and this will not be an effect strategy. DisclosuresNo relevant conflicts of interest to declare.